In order to induce an allergic reaction in an experimental animal, it has conventionally been necessary to first sensitize the animal, by immunizing it repeatedly with the antigen or allergen, prior to administering the antigen or allergen to obtain the desired reaction. Sensitizing large numbers of animals at the same time is not only laborious, but also troublesome, as responsiveness is tends to be variable among individual animals, so that it is difficult to obtain similar results from one experiment to the next.
Recently, the NC/Nga mouse has attracted attention as an animal model for atopic dermatitis. However, the dermatitis developed in this mouse is spontaneous, rather than induced, so that it does not develop as a result of the mouse being exposed to a specific allergen. This is inconvenient when researching cures for allergies. It does not help that the allergen which induces dermatitis in the mouse has not been identified.
Allergic reactions are initiated by the cross-linking of the high affinity immunoglobulin E receptor, FC.epsilon.RI, present on mast cells, by immunoglobulin E (IgE), once it has specifically bound to the allergen. This binding releases histamines and other mediators and leads to degranulation of the mast cells and, ultimately, the observed allergic response. To date, treatment has typically involved histamine antagonists or steroidal anti-inflammatory drugs. The discovery of more specific treatments is hampered by not having a reliable animal model.
An IgE transgenic mouse was obtained by Adamczewski et al. [Eur. J. Immunol. 21:617-626 (1991)]. The purpose sought to be achieved by this team was to develop an in vivo model system in which high levels of IgE could be achieved without antigenic stimulation. Accordingly, a gene coding for the heavy chain of IgE was introduced into the mouse. It was found that 100-fold higher titers of transgenic IgE were elicited, while levels of native IgE were not affected. Allergic responses also were not affected. The high titers of transgenic IgE were found to temporarily inhibit allergic responses, but it was concluded that, as only very low levels of mast cell binding are required to achieve an allergic response, then it would only require some dissociation of transgenic IgE to trigger a response. Antigen specific IgE was not obtained.
WO 95/15376 discloses humanized transgenic mice in which at least one human gene encoding the .alpha. chain of the FC.epsilon.RI receptor replaces expression of its murine analogue. This is sufficient to allow human IgE to bind the transgenic mast cells and trigger an allergic response. This model suffers in that the animal is not responsive to an antigen, human antibodies having to be administered in order to accomplish testing.